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PubMed2001

Development of an optimized interaction-mating protocol for large-scale yeast two-hybrid analyses.

BACKGROUND: Protein-protein interactions have decisive roles in almost all aspects of the structural and functional organization of cells. But in spite of the increasing amount of complete genome sequence data, the ability to predict protein function from sequences alone is limited. Therefore comprehensive analysis of protein-protein interactions, as derived from the yeast two-hybrid mating system, will yield valuable information for functional biology on a proteomic scale. RESULTS: We have developed an optimized interaction mating protocol for the yeast two-hybrid system, which gives increased mating efficiencies. This significantly reduces the effort and cost of cDNA library screening and allows multiple parallel approaches. Improved preincubation conditions before mating, and optimal cell densities and cell ratios enable almost quantitative mating of the yeast cells carrying the cDNA library. We have proved the applicability of this technology using 20 bait proteins to screen an Arabidopsis thaliana cDNA library, in spite of bait-dependent variations in mating efficiency. CONCLUSIONS: The improved yeast two-hybrid interaction-mating protocol presented here allows the multiple parallel screening of cDNA libraries. It can be carried out without specialized equipment and has the potential to be standardized and automated.

Arabidopsis↗

PubMed2003

Model building and model checking for biochemical processes.

A central claim of computational systems biology is that, by drawing on mathematical approaches developed in the context of dynamic systems, kinetic analysis, computational theory and logic, it is possible to create powerful simulation, analysis, and reasoning tools for working biologists to decipher existing data, devise new experiments, and ultimately to understand functional properties of genomes, proteomes, cells, organs, and organisms. In this article, a novel computational tool is described that achieves many of the goals of this new discipline. The novelty of this system involves an automaton-based semantics of the temporal evolution of complex biochemical reactions starting from the representation given as a set of differential equations. The related tools also provide ability to qualitatively reason about the systems using a propositional temporal logic that can express an ordered sequence of events succinctly and unambiguously. The implementation of mathematical and computational models in the Simpathica and XSSYS systems is described briefly. Several example applications of these systems to cellular and biochemical processes are presented: the two most prominent are Leibler et al.'s repressilator (an artificial synthesized oscillatory network), and Curto- Voit-Sorribas-Cascante's purine metabolism reaction model.

Biochemical Phenomena↗

PubMed2004

Requirements of a brain selective estrogen: advances and remaining challenges for developing a NeuroSERM.

Our goal is to develop therapeutic agents that prevent age-associated neurodegenerative disease such as Alzheimer's. To achieve this goal, we are building on extensive knowledge regarding mechanisms of estrogen action in brain and the epidemiological human data indicating that estrogen/hormone therapy reduces the risk of developing Alzheimer's disease when administered at the time of the menopause and continued over several to many years. The mechanisms of estrogen action in neurons provides a systematic mechanistic rationale for determining why estrogen therapy is efficacious for prevention of Alzheimer's disease and why it is not efficacious for long-term treatment of the disease. Our preclinical research plan is a hybrid of both discovery and translational research to develop a brain selective estrogen receptor modulator (SERM). We have termed such molecules NeuroSERMs to denote their preferential selectivity for activating estrogen mechanisms in brain. Our strategy to develop NeuroSERMs is threefold: (1) determine the target of estrogen action in brain, specifically the estrogen receptor in hippocampal and cortical neurons required for the neurotrophic and neuroprotective actions of estrogen; (2) develop NeuroSERM candidate molecules using three in silico discovery and design strategies and (3) determine the neurotrophic and neuroprotective efficacy of candidate molecules using neuronal responses predictive of clinical efficacy. Using an academic translational research model, a team of scientists with expertise in molecular biology, computational chemistry, synthetic chemistry, proteomics, neurobiology and mitochondrial function have been assembled along with state of the art technologies required to develop candidate NeuroSERM molecules.

Aged↗

PubMed2006

[Rational of oncological surgery in multimodality treatment of cancers].

The infiltrative cancers permanently swarm circulating cancer cells, and in 2006 it is no more possible to consider that localized cancer exists. So, we must question our self about the place of a treatment like surgery, which is localized in the time and in the space. Moreover, it is now proved that surgery increases the number of circulating cancers cells, gives a transient immunodepression which promotes cancer implantations, and that the cicatrisation stimulates growth factors, which act also on tumor growth. In spite of these deleterious effects, the oncological surgery stays an important tool by achieving an optimal cytoreductive surgery which facilitates the effect of the adjuvant treatments, by eliminating the vascular sanctuaries present in the center of any big tumor, and because it is a striking-force very localized in the space and in the time. The role of the oncological surgery must be integrated in the new aspect of the biology of the tumors and must take in account the recent improvements concerning functional imaging, genomic and proteomic. It is currently only one of the different compounds of the multimodality treatments for cancers, and its modalities, as its timing must be reconsidered. At last, considering the future technologies, we must elaborate the future modalities of the oncological surgery.

Chemotherapy, Adjuvant↗

PubMed2006

Characterization of the microtubule proteome during post-diapause development of Artemia franciscana.

The microtubule proteome encompasses tubulin and a diverse group of proteins which associate with tubulin upon microtubule formation. These proteins either determine microtubule organization and function or their activity is influenced by microtubule association. To characterize the microtubule proteome in Artemia franciscana, tubulin assembly was induced with taxol in vitro after 0 and 12 h of post-diapause development. Proteins obtained by extraction of microtubules with 0.5 M NaCl were electrophoresed in two-dimensional gels and analyzed by mass spectrometry. Fifty-five proteins were identified with 10 of these occurring at both developmental stages, and multiple isoforms were observed for some proteins of the Artemia proteome. Their functions include roles in membrane transport, metabolism, chaperoning and protein synthesis, thus reflecting physiological properties of encysted Artemia such as stress resistance and the ability to rapidly initiate post-diapause development. For example, chaperones may protect tubulin during encystment and facilitate folding in metabolically active embryos. Additionally, the interaction of metabolic enzymes with microtubules funnels reaction intermediates, potentially enhancing efficiency within biochemical processes. This study represents the first systematic characterization of a crustacean microtubule proteome. Although it is difficult to be certain that all protein associations documented herein occur in vivo, the results suggest how protein-protein interactions contribute to cytoplasmic organization while implying how Artemia embryos resist stress and remain capable of development once diapause terminates.

Animals↗

PubMed2006

Mapping the proteome of poplar and application to the discovery of drought-stress responsive proteins.

Poplar is the first forest tree genome to be decoded. As an initial step to the comprehensive analysis of poplar proteome, we described reference 2-D-maps for eight tissues/organs of the plant, and the functional characterization of some proteins. A total of 398 proteins were excised from the gels. About 91.2% were identified by nanospray LC-MS/MS, based on comparison with 260,000 Populus sp. ESTs. In comparison, reliable PMFs were obtained for only 51% of the spots by MALDI-TOF-MS, from which 43% (83 spots) positively matched gene models of the Populus trichocarpa genome sequence. Among these 83 spots, 58% matched with the same proteins as identified by LC-MS/MS, 21.7% with unknown function proteins and 19.3% with completely different functions. In the second phase, we studied the effect of drought stress on poplar root and leaf proteomes. The function of up- and down-regulated proteins is discussed with respect to the physiological response of the plants and compared with transcriptomic data. Some important clues regarding the way poplar copes with water deficit were revealed.

Databases, Protein↗

PubMed2000

Comparative analysis of brain proteins from p53-deficient mice by two-dimensional electrophoresis.

p53 is a tumor suppressor protein that regulates many cellular processes including the cell cycle, DNA repair, and apoptosis. It also serves as a critical regulator of neuronal apoptosis in the central nervous system (CNS). To elucidate the role of p53 in the CNS, brain proteins of p53 knock-out mice (p53-/-) were analyzed by two-dimensional gel electrophoresis (2-DE) and compared with those from p53 wild type (p53+/+) mice. Six types of brain tissue (temporal cortex, cerebellum, hippocampus, striatum, olfactory bulb, and cervical spinal cord) and other control tissues (lung and blood) from 18-week-old non-stress-induced mice were analyzed. The morphology of brains from p53-/- mice appeared to be normal and identical to that of p53+/+ mice, although lungs showed diffuse tumors that may have been caused by p53 deficiency. Comparative 2-D gel analysis showed that, on average, 7 of 886 spots from brain tissue were p53-/- specific, whereas 12 of 1008 spots from lung tissue were p53-/- specific. N-terminal amino acid sequence was determined for p53-/- specific proteins. In all brain tissues from p53-/- mice, a newly identified mouse mitochondrial NADH-ubiquinone oxidoreductase 24 kDa subunit showed decreased expression, and apolipoprotein A1 acidic forms showed increased expression. In addition, brain-type creatine kinase B chain and tubulin beta-5 N-terminal fragment were increased in the p53-/- cerebellum, and a new protein in mouse, hydroxyacylglutathione hydrolase (glyoxalase II) was decreased in the temporal cortex of p53-/- mice. The alterations in protein expression identified in this study may imply a p53-related brain function. This is the first proteomic analysis on the p53-/- mouse brain, and further information based on this study will provide new insights into the p53 function in the CNS.

Amino Acid Sequence↗

PubMed2005

The mysterious pulmonary brush cell: a cell in search of a function.

Brush cells, also termed tuft, caveolated, multivesicular, and fibrillovesicular cells, are part of the epithelial layer in the gastrointestinal and respiratory tracts. The cells are characterized by the presence of a tuft of blunt, squat microvilli (approximately 120-140/cell) on the cell surface. The microvilli contain filaments that stretch into the underlying cytoplasm. They have a distinctive pear shape with a wide base and a narrow microvillous apex. The function of the pulmonary brush cell is obscure. For this reason, a working group convened on August 23, 2004, in Bethesda, Maryland, to review the physiologic role of the brush (microvillous) cell in normal airways and alveoli and in respiratory diseases involving the alveolar region (e.g., emphysema and fibrosis) and airway disease characterized by either excessive or insufficient amounts of airway fluid (e.g., cystic fibrosis, chronic bronchitis, and exercise-induced asthma). The group formulated several suggestions for future investigation. For example, it would be useful to have a panel of specific markers for the brush cell and in this way separate these cells for culture and more direct examination of their function (e.g., microarray analysis and proteomics). Using quantitative analysis, it was suggested to examine the number and location of the cells in disease models. Understanding the function of these cells in alveoli and airways may provide clues to the pathogenesis of several disease states (e.g., cystic fibrosis and fibrosis) as well as a key for new therapeutic modalities.

Animals↗

PubMed2004

Complexity analysis of yeast proteome network.

Topological and compositional complexity of protein-protein networks is assessed in a variety of ways making use of graph theory and information theory. The methodology used is borrowed from mathematical chemistry and includes complexity descriptors such as substructure count, overall connectivity, walk count, and information on various vertex distributions. The approach is applied to the (incomplete) proteome of Saccharomyces cerevisiae containing 232 protein complexes of a total of 1,440 proteins. The proteome network and each of its nine functional subsets of protein complexes are disconnected graphs, containing a number of noninteracting species and a major component. A weighted edge between two vertices in these graphs stands for the number of shared proteins between the respective complexes. The major component is a highly connected, 'small-world' network, in which the average vertex distance between protein complexes does not exceed 2.2 (2.4 for the entire proteome), whereas the maximum distance does not exceed 4 (or 5 for the proteome). The vertex degree distribution in the major proteome component with 199 complexes follows the power law P(k) approximately k(-gamma), with gamma approximately = 1.7. The analysis of the functional organization of the yeast proteome has shown that, for any pair of biological functions, there always exist many proteins that can perform both functions. The potential application of the quantitative proteome descriptors discussed includes quantitative relationships between the structure and biological action of dynamic protein complexes in changing environment, identification of targets for markers/drugs, as well as system analysis and comparative studies of proteomes.

Fungal Proteins↗

PubMed2026

Cardiac remodelling and dysfunction in cancer patients receiving cardiotoxic therapies: proteomic and metabolomic profiling.

BACKGROUND AND AIMS: The objective of this study was to define the relationships between the circulating proteome and metabolome with cardiac structure and function in patients with breast cancer receiving cardiotoxic therapies. METHODS: Proteomics and metabolomics profiling was performed in a longitudinal, prospective cohort study of breast cancer patients receiving anthracyclines and/or trastuzumab, using the Olink Explore 3072 platform and rapid liquid chromatography-mass spectrometry, respectively. Multivariable linear mixed-effect models evaluated the contemporaneous (same visit) and lagged (subsequent visit) associations between repeated measures of individual proteins or metabolites with quantitative echocardiographic measures of cardiac structure [left ventricular (LV) mass and left atrial volume index] and function [LV ejection fraction (LVEF), longitudinal and circumferential strain, E/e', and ventricular-arterial coupling]. Cox regression and pathway enrichment analyses were conducted for biomarkers demonstrating significant associations with cardiac function. RESULTS: Across 547 breast cancer participants (median age 50 years), 203 unique proteins and 16 unique metabolites were significantly associated with measures of cardiac structure and function in contemporaneous and lagged analyses. Notably, cathepsin C was associated with LVEF [false discovery rate (FDR), P = .017], longitudinal strain (FDR, P = .046), left atrial volume index (FDR, P = .035), and incident cardiac dysfunction, defined by an LVEF decline ≥10% to <50% (hazard ratio .61, 95% confidence interval .41, .90). The 147 proteins associated with cardiac function were enriched in biological processes reflective of protein deubiquitination, protein modification by small protein removal, macromolecule catabolic processes, and global metabolic pathways. Individual metabolites significantly associated with cardiac function (LVEF, longitudinal strain) included n-acetylglutamine, aspartic acid, acetylasparagine, alanyl-alanine, and prolyl-glycine (FDR, P-value < .001), and belonged to amino acids and derivatives and peptides. CONCLUSIONS: These findings provide translational insights into cancer therapy-related cardiac dysfunction and remodelling and identify potential new biomarkers of cardiotoxicity. There is an important need for validation of these findings and a deeper understanding of the biology of these biomarkers.

Humans↗

PubMed2005

Universal biases in protein composition of model prokaryotes.

The levels of cellular organization in living organisms are the results of a variety of selection pressures. We have investigated here the final outcome of this integrated selective process in proteins of the best known microbial models Escherichia coli, Bacillus subtilis, and Methanococcus jannaschii, supposed to have undergone separate evolution for more than 1 billion years. Using multivariate analysis methods, including correspondence analysis, we studied the overall amino acid composition of all proteins making a proteome. Starting from and further developing previous results that had pointed out some general forces driving the amino acid composition of the proteomes of these model bacteria, we explored the correlations existing between the structure and functions of the proteins forming a proteome and their amino acid composition. The electric charge of amino acids measured against hydrophobicity creates a highly homogeneous cluster, made exclusively of proteins that are core components of the cytoplasmic membrane of the cell (integral inner membrane proteins). A second bias is imposed by the G+C content of the genome, indicating that protein functions are so robust with respect to amino acid changes that they can accommodate a large shift in the nucleotide content of the genome. A remarkable role of aromatic amino acids was uncovered. Expressed orphan proteins are enriched in these residues, suggesting that they might participate in a process of gain of function during evolution.

Amino Acids↗

PubMed2004

Genome-based proteomics.

Protein-protein interactions play crucial roles in various biological pathways and functions. Therefore, the characterization of protein levels and also the network of interactions within an organism would contribute considerably to the understanding of life. The availability of the human genome sequence has created a range of new possibilities for biomedical research. A crucial challenge is to utilize the genetic information for better understanding of protein distribution and function in normal as well as in pathological biological processes. In this review, we have focused on different platforms used for systematic genome-based proteome analyses. These technologies are in many ways complementary and should be seen as various ways to elucidate different functions of the proteome.

Chromatography, Liquid↗

PubMed2005

The DnaJ-domain protein RME-8 functions in endosomal trafficking.

Through a proteomic analysis of clathrin-coated vesicles from rat liver we identified the mammalian homolog of receptor-mediated endocytosis 8 (RME-8), a DnaJ domain-containing protein originally identified in a screen for endocytic defects in Caenorhabditis elegans. Mammalian RME-8 has a broad tissue distribution, and affinity selection assays reveal the ubiquitous chaperone Hsc70, which regulates protein conformation at diverse membrane sites as the major binding partner for its DnaJ domain. RME-8 is tightly associated with microsomal membranes and co-localizes with markers of the endosomal system. Small interfering RNA-mediated knock down of RME-8 has no influence on transferrin endocytosis but causes a reduction in epidermal growth factor internalization. Interestingly, and consistent with a localization to endosomes, knock down of RME-8 also leads to alterations in the trafficking of the cation-independent mannose 6-phosphate receptor and improper sorting of the lysosomal hydrolase cathepsin D. Our data demonstrate that RME-8 functions in intracellular trafficking and provides the first evidence of a functional role for a DnaJ domain-bearing co-chaperone on endosomes.

Amino Acid Sequence↗

PubMed2001

Analysis of the plant proteome.

For many years the analysis of plant proteomes has been restricted to the construction of descriptive catalogues or the search for markers. The analysis of plant proteomes is now gaining a functional dimension, however, because the focus has shifted onto well-defined plant-specific tissues and organelles, the simultaneous mining of proteomic and physiological data and specific methodological efforts.

Biotechnology↗

PubMed2005

Proteomic changes associated with inactivation of the Candida glabrata ACE2 virulence-moderating gene.

Inactivation of the gene encoding the transcriptional activator Ace2 in the fungal pathogen Candida glabrata results in an almost 200-fold increase in virulence characterised by acute mortality and a massive over-stimulation of the pro-inflammatory arm of the innate immune system. In this study we have adopted a proteomics approach to identify cellular functions regulated by C. glabrata Ace2 that might contribute to this increase in virulence. A two-dimensional polyacrylamide gel electrophoresis map of the C. glabrata proteome was constructed. We identified a total of 123 proteins, 61 of which displayed reproducible and statistically significant alterations in their levels following inactivation of ACE2. Of these, the levels of 32 proteins were elevated, and 29 were reduced in ace2 cells. These data show that Ace2 influences metabolism, protein synthesis, folding and targeting, and aspects of cell growth and polarisation. Some of these functions are likely to contribute to the effects of Ace2 upon the virulence of C. glabrata.

Candida glabrata↗

PubMedDate not supplied

Defining the balance of risk and benefit in the era of genomics and proteomics.

The ability to measure the function of genes and proteins has spawned the construct of personalized medicine, in which patients' own risks and preferences are used to choose diagnostic and therapeutic strategies. The complexity of clinical data required to guide personalized medicine calls for improvements in our system of clinical research, including (1) overhauling it to produce networks that can do adequate-size pragmatic trials; (2) synchronization of regulatory and payment systems to encourage adequate studies; and (3) an investment in education of providers and patients to improve the understanding of the probabilistic predictions forming the basis of personalized medicine.

Clinical Trials as Topic↗

PubMed2004

Functional genomics analysis of Singapore grouper iridovirus: complete sequence determination and proteomic analysis.

Here we report the complete genome sequence of Singapore grouper iridovirus (SGIV). Sequencing of the random shotgun and restriction endonuclease genomic libraries showed that the entire SGIV genome consists of 140,131 nucleotide bp. One hundred sixty-two open reading frames (ORFs) from the sense and antisense DNA strands, coding for lengths varying from 41 to 1,268 amino acids, were identified. Computer-assisted analyses of the deduced amino acid sequences revealed that 77 of the ORFs exhibited homologies to known virus genes, 23 of which matched functional iridovirus proteins. Forty-two putative conserved domains or signatures were detected in the National Center for Biotechnology Information CD-Search database and PROSITE database. An assortment of enzyme activities involved in DNA replication, transcription, nucleotide metabolism, cell signaling, etc., were identified. Viruses were cultured on a cell line derived from the embryonated egg of the grouper Epinephelus tauvina, isolated, and purified by sucrose gradient ultracentrifugation. The protein extract from the purified virions was analyzed by polyacrylamide gel electrophoresis followed by in-gel digestion of protein bands. Matrix-assisted laser desorption ionization-time of flight mass spectrometry and database searching led to identification of 26 proteins. Twenty of these represented novel or previously unidentified genes, which were further confirmed by reverse transcription-PCR (RT-PCR) and DNA sequencing of their respective RT-PCR products.

Animals↗

PubMed2026

Large-scale proteomics profiling of peripheral blood of DM1 patients identifies biomarkers for disease severity and functional capacity.

BackgroundMyotonic Dystrophy Type 1 (DM1), the most common genetic neuromuscular disorder in adults, poses significant challenges for drug development due to its multisystem nature and high clinical variability in symptoms and disease progression. With a growing number of therapies entering clinical trials, this study addresses the urgent need for biomarkers that can serve as surrogate endpoints.MethodsWe profiled 437 serum samples from adult DM1 patients collected at two timepoints of the OPTIMISTIC trial using bottom-up mass spectrometry with data-independent acquisition. Associations between protein expression, the disease-causing CTG-repeat and 25 clinical outcome measures were studied using linear mixed-effect models. All key study findings were validated in an independent cohort of 69 DM1 patients and 10 healthy controls.ResultsOf the 259 identified proteins, 161 showed significant associations with the CTG-repeat length (FDR < 5%). Hypogammaglobulinemia was confirmed and shown to be worse in severely affected patients. A strong proteomic signature was associated with clinical measures of functional capacity, with the 6-Minute Walk Test showing the strongest signal (70 associations, FDR < 5%). These novel associations reveal a compelling link between chronic inflammation and reduced functional capacity. A machine learning algorithm identified a minimal set of 13 proteins robustly reflecting both the underlying genetic defect and functional capacity.ConclusionsDM1 induces a broad disease fingerprint in the serum proteome, predominantly affecting proteins of the immune system. A carefully selected panel of proteins showed the greatest potential to meet the statistical criteria required for surrogate endpoints in clinical trials.

Humans↗